Human cytomegalovirus (HCMV) is a widespread pathogen that is the leading viral cause of birth defects and a major cause of morbidity and mortality in adults who are immunocompromised. Although HCMV has not been shown to play a direct causative role in human cancer, it impacts cancer patients as an opportunistic infection, and several of its gene impacts exhibits oncogenic or mutagenic activity or modulate cell cycle progression, influencing cell growth. Its interaction with an infected host is complex. HCMV can undergo latency in some cell types and actively replicate to produce infectious progeny in a variety of other cell types. Given its prominence as a human pathogen, it is essential that we continue to advance our understanding of the molecular mechanisms that underlie HCMV replication and pathogenesis. The long-term objectives of this research program are to elucidate the role of cellular genes in HCMV replication and to identify the differences in the interaction of HCMV with its host cell that lead to productive replication as compared to latency. This proposal builds on preliminary studies in which cellular mRNAs whose steady state levels are modulated by HCMV have been identified, and it includes two specific aims: (1) determine the mechanism by which HCMV alters cellular gene expression, and elucidate the physiological consequences of these changes; and (2) assay HCMV gene expression in latently infected cells, and investigate the functions of viral genes that are identified. This research program will benefit from technical and intellectual synergies, as well as from the opportunity for comparative studies, provide by the program project grant format.